The immune response to protein antigens depends on processing by antigen presenting cells and subsequent presentation of peptides to specific T cells by molecules of the MHC. In rheumatoid arthritis (RA) there is much evidence implicating a positive genetic association of the disease with several alleles of the DRB1 gene, characterised by a common amino acid sequence at position 70-74 ("shared epitope"). The most frequent of these alleles is DRB1*0401 with the sequence QKRAA, which is also present in the E. coli protein DnaJ. DnaJ and DnaK, a member of the HSP70 family, or their homologs in other species, together form an important chaperone machinery in bacteria and higher organisms, including man. It was proposed that the motif QKRAA might be involved in binding between DnaJ and DnaK, and also in binding of QKRAA-containing DR $-chains to the human heat shock cognate protein HSC70. We used a T cell clone with a restriction pattern similar to the genetic association of RA, being specific for an epitope of the "chain of the human acetylcholine receptor (AChR). It reacted with synthetic peptides presented by murine P388.D1 expressing the human DRA and DRB1*0401 (71Lys) or DRB1*0408 (71Arg), with slight preference for 0408. In contrary, the recombinant "-chain (r1-437) or AChR obtained from human muscle extracts were much better presented by 0401. This preference depended entirely on the presence of E. coli DnaK or human HSC70 in the antigen preparations; the response was lost, if HSP70 molecules were removed, and reconstituted by their addition. We conclude that efficient processing of the long protein requires the presence of a member of the HSP70 family, which besides protecting the epitope, interacts intracellularly well with 0401, but less well with 0408 $-chains, and thus participates in the process of peptide loading. This mechanism might be of importance for immune responses against foreign antigens (advantage of DRB1*0401) as well as against autoantigens (disadvantage of DRB1*0401).